The invention relates to a tandem mass spectrometer and a method for scanning daughter ion spectra which uses a quadrupole mass spectrometer for selection of parent ions and another one for the measurement of the daughter ions.
The invention consists of not using a conventional third quadrupole filter as a collision cell for fragmentation of the parent ions but an ion guide system with helically coiled wires, especially in the form of a double helix, in which the ions can be completely decelerated and can be actively fed to the outlet aperture.
Quadrupole mass spectrometers can be traced back to Wolfgang Paul. In patent DE 944 900 (U.S. Pat. No. 2,939,952) by Paul and Steinwedel from the priority year 1953 both the quadrupole mass filter and the quadrupole ion trap are described. Knowledge of quadrupole mass spectrometry is assumed here.
Tandem mass spectrometry is the measurement of daughter ions in a second mass spectrometer, whereby the daughter ions are obtained from parent ions which are selected in a first mass spectrometer. Usually the daughter or fragment ions are generated in collisionally induced processes with gas molecules between the first and second mass spectrometer, but other types of fragmentation are also known for the parent ions.
Tandem mass spectrometry with quadrupole filters has been known for about 20 years (U.S. Pat. No. 4,234,791, C. G. Enke, R. A. Yost and J. D. Morrison; U.S. Pat. No. 4,329,582, J. B. French and P. H. Dawson) and normally uses a technique which is based on xe2x80x9ctriple quadrupolesxe2x80x9d or xe2x80x9ctriple quadsxe2x80x9d. The first quadrupole serves as a mass spectrometer for selection of the parent ions, the second quadrupole serves as a fragmentation chamber with injection of the selected parent ions into a collision gas, and the third quadrupole serves as a mass analyzer for the resulting daughter or fragment ions.
The first quadrupole mass spectrometer is operated at an RF voltage with superimposed DC voltage, so that a small mass range can be selected (or more precisely: a range for the mass-to-charge ratios which can solely be determined by mass spectrometry). The second quadrupole, on the other hand, is operated only at an RF voltage without any superimposed DC voltage so it only acts as a guidance system for the ions. The ions injected at approx. 20 to 30 electron Volts diffuse very strongly in the collision gas so the guidance system for the ions (also referred to as ion guide system) prevents ion losses. The third quadrupole is again operated with superimposed DC voltage, it filters out ions of a single mass (or rather of a single mass-to-charge ratio). By changing voltages the filtered mass can be altered and in this way an entire spectrum can be scanned across all the masses.
A triple quadrupole mass spectrometer has proved particularly successful for quantitative analysis of mixtures of substances, whereby the mixtures are separated by gas chromatography or liquid chromatography and are fed to the ion source of such a spectrometer. Since the substances are known in principle, it is not necessary to measure the daughter ion spectra entirely. One can leave the mass spectrometer set so that the first quadrupole mass spectrometer admits a characteristic ion of a substance, in the second quadrupole this then produces daughter ions, of which, however, in the third quadrupole again only a characteristic daughter ion is measured. For the measurement of this substance there is therefore no scan by the third quadrupole from mass to mass but both filters remain open constantly. This produces a high transmission for the ions and a high selectivity for the substance sought.
To improve the measuring accuracy from a quantitative aspect one can add a reference substance, preferably an isotope-marked derivative of the test substance; one then measures both substances at the same retention time. By simply switching over the two admission windows of the quadrupole filters for the two substances one can determine their ratio. Here too it is not the entire mass range which is scanned, there is only a switch to and fro between the two admission states.
There are also other highly interesting methods of operation for triple quadrupole mass spectrometers but these will not be discussed individually here.
The triple quadrupole mass spectrometers known nowadays still have, despite many years of development, considerable disadvantages which are to be found in the principle of the equipment. For triple quadrupole mass spectrometers there is a fundamental problem: if one increases the collision yield of daughter ions by increasing the collision gas density in the center quadrupole, one increases the velocity inhomogeneity of the daughter ions at the output from that quadrupole, which leads to inferior transmission when passing to the third quadrupole and to an inferior mass resolution in that quadrupole mass spectrometer. The rods of this analytical quadrupole mass spectrometer must therefore be very long in order to achieve better mass filtering with a long dwell time also for faster ions in that quadrupole field; the inferior transmission on passing to that quadrupole can, however, not be improved. Long quadrupole systems are also difficult and expensive to manufacture.
To solve this fundamental problem a method has become known (Sciex Inc., Thornhill, Canada), which keeps the collision gas density relatively low in the second quadrupole and simultaneously increases the fragmentation through excitation of the ion oscillations in that quadrupole with a resonance dipole alternating field for the parent ions perpendicular to the direction of ion flight. This can be performed with an additional alternating voltage across two opposite poles of the quadrupole. Due to this additional excitation the yield of daughter ions is improved but the fundamental problem of the triple quadrupole mass spectrometer is not completely solved.
The six-dimensional space of spatial and pulse coordinates of particles is referred to as the xe2x80x9cphase spacexe2x80x9d. In an ion beam the spatial and pulse coordinates of all the ions fill out a certain part of the phase space and this part is referred to as the xe2x80x9cphase space volumexe2x80x9d. The fundamental problem of any triple quadrupole mass spectrometer is that in the collision quadrupole the phase space volume of the ions is increased and the analytical quadrupole mass spectrometer can only efficiently separate ions of a small phase space volume. The mass resolution of a third quadrupole mass spectrometer therefore is quite essentially dependent on the spatial and velocity distribution of the injected ions.
According to the laws of physics a reduction in phase space volume cannot be achieved by ion-optical means but only by cooling the ion plasma of the ion beam, for example by cooling in a damping gas. Such cooling of the ions by a damping gas (at the expense of time) is, for instance, known from RF quadrupole ion traps. Cooling of the ions of the center quadrupole field fails, however, due to the fact that the ions require a residual forward velocity in order to reliably fly out of the field again.
It is the objective of this invention to find a device in which injected ions are not only fragmented but also cooled so that their phase space volume is reduced. It should then be possible to inject the ions as a fine beam with homogenous energy into a quadrupole mass spectrometer acting as an analyzer.
The invention consists of usingxe2x80x94for fragmentation of the parent ionsxe2x80x94an ion guide system with at least one helically coiled wire pair in which the motions of all the ions can be completely damped after their fragmentation due to a high gas density so that they practically come to rest in the gas and collect along the axis of the ion guide system. In such an ion guide system the ions must then be actively guided to the end of the ion guide system by an extra thrust, extracted there and be injected into the analyzing quadrupole mass spectrometer.
An ion guide system which is only comprised of one coiled pair of wires in the form of a double helix is particularly suitable.
Such an ion guide system in the form of a double helix is described in detail in U.S. Pat. No. 5,572,035. It is comprised of two wires coiled helically around the same axis which are connected to the two phases of an RF voltage supply. This double helix can take the form of a cylinder, but also that of a truncated cone or a trumpet, whereby the wall is created by the coils of wire. In that structure a pseudo potential is generated which drives the ions back to the wall when they approach. Along the axis there is a trough of this pseudo potential. The pseudo potential acts on positive and negative ions in the same way. The pseudo potential arises as a time integral over the attracting and repelling forces of the inhomogeneous electrical alternating field of forces on an oscillating particle in the vicinity of the wires. The pseudo potential of a double helix array can be made extremely high, much higher than is possible for ion guide systems made from pole rods.
A reduction in phase space volume particularly depends on matching the length of the ion guide system and the pressure of the damping gas to one another in such a way that the injected ionsxe2x80x94apart from thermal diffusion motionsxe2x80x94come to rest completely in the gas and thereby collect in the trough of the pseudo potential, that is, along the axis of the ion guide system. Since the ions come to rest in the gas it is necessary, by contrast with the previous use of ion guide systems, to actively drive the ions to the end of the ion guide system.
The ions must be injected into the ion guide system with a kinetic energy which is sufficient for collisionally induced fragmentation. The relatively slow guidance (in a few milliseconds) of the ions, which are then practically at rest, to the end of the ion guide system also helps to cool the daughter ions and cause short-lived, highly excited daughter ions to decompose. As a result a largely background noise-free daughter ion spectrum is obtained in the analytical quadrupole mass spectrometer which is not contaminated by scattered ions from ion decompositions during flight in the quadrupole mass spectrometer.
Filling with gas can be accomplished by operating the ion guide system in a separate vacuum chamber, which is at a required pressure of between 0.01 and 100 Pascal (preferably between 0.1 and 10 Pascal), or by at least partially providing the ion guide system with an envelope so that only the envelope is filled with gas. The gas can then flow through the envelope and thus longitudinally through the double helix.
The active forward thrust of the damped ions can take place in several different ways: (1) The ions can be most simply driven forward by the admitted gas itself if the gas is admitted at the beginning of an envelope round the ion guide system and flows through the ion guide system to the end. (2) If the ion guide system is made conical the ions can be provided with a gentle forward thrust if the cone opens toward the ion outlet, which is not preferred here though. (3) The ion guide system can be provided with a weak axial DC field which guides the ions to the end of the guide system. For example, if the helical wires are each supplied with a DC voltage across both ends a voltage drop will be created along the axis of the ion guide system. It is expedient to make the wires of the double helix from resistance wire. A very weak field of only approx. 0.01 to 1 volt per centimeter (preferably about 0.1 V/cm) is sufficient to drive the ions forward.
Several forward thrust systems can also act simultaneously. If the ion guide system is, for instance, open in a conical shape toward the ion injection (quite definitely a very favorable case), a pseudo potential is created which weakly drives the ions back to the entrance. However, this effect can be overcompensated by an axial DC voltage field.
The ions which are located at the end of the double helix in a fine current thread can now be injected directly into the analytical quadrupole mass spectrometer by keeping the axial potential of the downstream quadrupole mass spectrometer several volts below the axial potential of the double helix. However, this configuration is not particularly advantageous because it is expedient to operate the analytical quadrupole mass spectrometer in its own chamber with a much better vacuum.
A drawing lens is an ion-optical lens which also imparts upon the ions an acceleration at the same time as focusing (or defocusing). Both sides of the lens are therefore at different potentials. This is different from a so-called Einzel lens, which only exercises a focusing (or defocusing) effect, but no acceleration; the Einzel lens thus always has the same potential on both sides. Drawing lenses and Einzel lenses are generally comprised of concentric apertured diaphragms at a fixed distance from one another. A drawing lens system is a system comprised of at least one ion-optical lens in which there is at least one drawing lens.
A drawing lens system can extract the ions from the ion guide system very efficiently if the potential of the second apertured diaphragm extends through the hole of the first apertured diaphragm into the ion guide system. The first apertured diaphragm is approximately at the axial potential of the ion guide. The hole in the second apertured diaphragm should favorably have a smaller diameter than the hole of the first apertured diaphragm. It is also favorable to design the last three diaphragms of a drawing lens system as an Einzel lens, which handles the required focusing.
Since in the ion guide system a gas pressure prevails which is intentionally damping the ion motions but a better vacuum has to prevail in the analytical quadrupole mass spectrometer, it is useful for the two to be in separate vacuum chambers. Then it is expedient to integrate the apertured diaphragm of the drawing lens system with the smallest hole into the wall between the vacuum chambers with a gastight seal. The hole diameter can be approx. 0.5 millimeters. To maintain a good pressure differential it is helpful if the hole forms a small channel. Two apertured diaphragms of the drawing lens system can also be used to generate a differential pump stage by evacuating separately between those two apertured diaphragms.
In addition it is helpful for maintaining a good pressure in the analytical quadrupole mass spectrometer if in the ion guide system the pressure of the damping gas decreases toward the end. This can be achieved if the gas flows in at the beginning and if a pressure drop is created with openings in the envelope along the ion guide system.
Upstream of the ion guide system for ion fragmentation there is an ion selecting quadrupole mass spectrometer which, in turn, can be positioned in a separate vacuum chamber. Parent ions for generating daughter ions can be selected in various ways. Consequently one can select all isotopic ions of a substance with the same charge or only a single isotopic type (xe2x80x9cmonoisotopicxe2x80x9d ions). It is also possible to connect a drawing lens system, which can be used to accelerate the ions on the one hand and to separate the vacuum chambers on the other, between the selective quadrupole mass spectrometer and the ion guide system.